Protocol 1: A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-Mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment with Osimertinib (AZD9291, Tagrisso) Project summary: We have enrolled 34 patients in this protocol. 16 patients underwent LAT procedure. Since we have mandatory biopsies during PFS1 pre- and post-resistance to osimertinib, we have developed a proteo-genomics analysis plan to identify key mechanisms of resistance.We have conducted whole exome sequencing (WES) and transcriptome sequencing (RNAseq) on pre-treatment and post-progression tumor samples of 14 patients. We have analyzed this data and uncovered novel mechanisms of resistance to osimertinib. We have identified MET amplification, C797S mutation, SCLC transformation among the mechanisms of resistance to osimertinib. Interestingly, significant heterogeneity in MET amplification was uncovered by multi-region sequencing. A manuscript on the data from these 14 patients is in preparation. Protocol 2: Tissue Procurement and Natural History Study of Patients with Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Extrapulmonary Small Cell Cancer, Pulmonary Neuroendocrine Tumors, and Thymic Epithelial Tumors. Project summary: This protocol is actively recruiting. 296 patients have been recruited. This is the only study for tissue procurement in our thoracic oncology clinic for patients of all histologies except mesothelioma in which patients can get enrolled even if they are not enrolled in any treatment protocol at the NIH. There is a separate such protocol for mesothelioma (PI- Dr. Hassan). The tumor tissue acquired from this protocol will be used for validation of potential biomarkers of treatment response and resistance. Candidates will primarily be from the basic and pre-clinical proteomics studies performed in our laboratory. This protocol will also allow correlative studies for all other treatment protocols conducted in our clinic. Protocol 3: A pilot study of inpatient hospice with procurement of tissue on expiration in thoracic malignancies. Project summary: We have performed six autopsies on this protocol. It is quite challenging to acquire tumor tissue from various sites of metastatic disease in patients. However, such a tissue bank is a unique resource for various research studies. A rapid autopsy protocol enables viable tissue procurement for generation of cell lines, creation of patient-derived xenografts (PDX), and proper storage and fixation for research studies. This requires a close collaboration with pathologists, pain and palliative care specialists, nurses and social workers. The NIH Clinical Center has all the resources needed to conduct such a study. The patients who visit the Clinical Center are also very motivated and often want to contribute to research in oncology at the end of their life. The overall goal of this protocol is to examine the extent of tumor heterogeneity in various thoracic malignancies and how it influences targeted treatment response. The proteo-genomic studies proposed are actively being conducted in our and in our collaborators' laboratories within the intramural program. We have performed sequencing of 52 exomes and 30 transcriptomes to interrogate both intra-tumor and inter-tumor heterogeneity in these patients. We are currently analyzing the genomics data. The same sites of disease that underwent next-generation sequencing will undergo mass spectrometry-based proteomics to examine the heterogeneity at the protein level and in signaling pathways. The genomics and the proteomics studies on these rapid autopsy samples will be correlated to get a comprehensive analysis of the extent of heterogeneity and how it may have influenced treatment response in these patients. We have successfully conducted autopsies in 18 patients. 1 more patient is enrolled in this study and being followed. Protocol 4: Pilot trial of molecular profiling and targeted therapy for advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic malignancies. Project summary: Currently this is closed to accrual for new patients on all treatment arms, except for patients with potential EGFR germline mutations. Such patients are enrolled and tested for EGFR germline mutations. We are following several members of two families harboring the EGFR germline mutation, T790M. The detection of germline EGFR mutation and follow up of families with the mutation will soon be a stand-alone protocol. This is a biomarker derived multi-arm, multi-histology phase II basket trial. The feasibility of this basket trial design was not assessed properly when this trial was started. This design assesses the effects of a targeted agent against a specific molecular aberration while agnostic of the histologic context. Mutations or amplifications in 11 genes were used to assign patients to 1 of 5 biomarker matched treatment groups. In addition, around 200 genes were tested for mutations by next generation sequencing (NGS) technology. The infrastructure for such targeted sequencing analysis is available in the intramural program. The sequencing studies were performed in the Laboratory of Pathology (Dr. Mark Raffeld) and the Genetics Branch (Dr. Paul Meltzer). Germline EGFR mutant patients in this protocol constitute a unique subset of patients with germline predisposition of lung adenocarcinoma. There are few clinical protocols of this subset of patients in this country. Unlike other protocols elsewhere for germline EGFR mutation detection, our protocol allows clinical follow up of these patients with annual high resolution CT scan, including all interventions necessary to follow abnormal scans.